Universität zu Köln

Kirabali, Tunahan ORCID: 0000-0002-7554-3371, Rigotti, Serena, Siccoli, Alessandro, Liebsch, Filip ORCID: 0000-0002-0955-8065, Shobo, Adeola, Hock, Christoph, Nitsch, Roger M., Multhaup, Gerhard and Kulic, Luka (2019). The amyloid-beta degradation intermediate A beta 34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer's disease. Acta Neuropathol. Commun., 7 (1). LONDON: BMC. ISSN 2051-5960

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Abstract

An impairment of amyloid beta-peptide (A beta) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer's disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of A beta 40 and A beta 42 results in the formation of a common A beta 34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of A beta 34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of A beta 34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, A beta 34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated A beta 34 immunoreactivity was largely lost. A beta 34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with A beta 40, but not with A beta 42 levels. Moreover, a significantly decreased A beta 34/A beta 40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of A beta 40 to A beta 34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of A beta 34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of A beta 34 levels upon treatment with recombinant A beta 40 peptides while A beta 34 production was impaired when A beta 40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that A beta 34 is generated by a novel BACE1-mediated A beta clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kirabali, Tunahan UNSPECIFIED orcid.org/0000-0002-7554-3371 UNSPECIFIED Rigotti, Serena UNSPECIFIED UNSPECIFIED UNSPECIFIED Siccoli, Alessandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebsch, Filip UNSPECIFIED orcid.org/0000-0002-0955-8065 UNSPECIFIED Shobo, Adeola UNSPECIFIED UNSPECIFIED UNSPECIFIED Hock, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Nitsch, Roger M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Multhaup, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Kulic, Luka UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-124780
DOI:	10.1186/s40478-019-0846-8
Journal or Publication Title:	Acta Neuropathol. Commun.
Volume:	7
Number:	1
Date:	2019
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	2051-5960
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language A-BETA; NEUROPATHOLOGIC ASSESSMENT; NATIONAL INSTITUTE; PEPTIDE; DEFICIENCY; EXPRESSION; ANGIOPATHY; GUIDELINES; CLEARANCE; PATHOLOGY Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12478